Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice

The pulmonary endothelin (ET) system has been implicated in the pathogenesi s of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans, However, the etiologic role of ET-1 in these diseases has not y et been established. We recently demonstrated that ET-1 transgenic mice, ge nerated using the human prepro-ET-l expression cassette including the cis-a cting transcriptional regulatory elements, had predominant transgene expres sion in lung, brain, and kidney, We used these mice in the present study to analyze the pathophysiologic consequences of longterm pulmonary overexpres sion of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predo minantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpressi on of ET-1 may be a central event in the pathogenesis of lung diseases asso ciated with fibrosis and chronic inflammation, such as pulmonary fibrosis a nd bronchiolitis.